VCV000098134.41 - ClinVar

NM_002087.4(GRN):c.328C>T (p.Arg110Ter)

Germline

Classification

The aggregate germline classification for this variant, typically for a monogenic or Mendelian disorder as in the ACMG/AMP guidelines, or for response to a drug. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the aggregate classification.

(8)

Stars represent the aggregate review status, or the level of review supporting the aggregate germline classification for this VCV record. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status. The number of submissions which contribute to this review status is shown in parentheses.

Pathogenic

criteria provided, multiple submitters, no conflicts

Somatic

No data submitted for somatic clinical impact

Somatic

No data submitted for oncogenicity

Variant Details

Identifiers

NM_002087.4(GRN):c.328C>T (p.Arg110Ter)

Variation ID: 98134 Accession: VCV000098134.41

Type and length

single nucleotide variant, 1 bp

Location

Cytogenetic: 17q21.31 17: 44349730 (GRCh38) [ NCBI UCSC ] 17: 42427098 (GRCh37) [ NCBI UCSC ]

Timeline in ClinVar

	First in ClinVar Help The date this variant first appeared in ClinVar with each type of classification.	Last submission Help The date of the most recent submission for each type of classification for this variant.	Last evaluated Help The most recent date that a submitter evaluated this variant for each type of classification.
Germline	Feb 20, 2014	Oct 20, 2024	Oct 1, 2023

HGVS

Nucleotide	Protein	Molecular consequence
NM_002087.4:c.328C>T MANE Select Help Transcripts from the Matched Annotation from the NCBI and EMBL-EBI (MANE) collaboration.	NP_002078.1:p.Arg110Ter	nonsense
NC_000017.11:g.44349730C>T
NC_000017.10:g.42427098C>T
NG_007886.1:g.9608C>T
LRG_661:g.9608C>T
LRG_661t1:c.328C>T

... more HGVS ... less HGVS

Protein change

R110*

Other names

Canonical SPDI

NC_000017.11:44349729:C:T

Functional consequence Help The effect of the variant on RNA or protein function, based on experimental evidence from submitters.

loss_of_function_variant; Sequence Ontology [ SO:0002054]

Global minor allele frequency (GMAF) Help The global minor allele frequency calculated by the 1000 Genomes Project. The minor allele at this location is indicated in parentheses and may be different from the allele represented by this VCV record.

Allele frequency Help The frequency of the allele represented by this VCV record.

The Genome Aggregation Database (gnomAD), exomes 0.00000

Exome Aggregation Consortium (ExAC) 0.00001

Trans-Omics for Precision Medicine (TOPMed) 0.00001

Links

ClinGen: CA225231 dbSNP: rs63750411 VarSome

Genes

Gene	OMIM	ClinGen Gene Dosage Sensitivity Curation		Variation Viewer Help Links to Variation Viewer, a genome browser to view variation data from NCBI databases.	Related variants
Gene	OMIM	HI score Help The haploinsufficiency score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.	TS score Help The triplosensitivity score for the gene, curated by ClinGen’s Dosage Sensitivity Curation task team.		Within gene Help The number of variants in ClinVar that are contained within this gene, with a link to view the list of variants.	All Help The number of variants in ClinVar for this gene, including smaller variants within the gene and larger CNVs that overlap or fully contain the gene.
GRN		-	-	GRCh38 GRCh37	657	698

Conditions - Germline

Condition Help The condition for this variant-condition (RCV) record in ClinVar.	Classification Help The aggregate germline classification for this variant-condition (RCV) record in ClinVar. The number of submissions that contribute to this aggregate classification is shown in parentheses. (# of submissions)	Review status Help The aggregate review status for this variant-condition (RCV) record in ClinVar. This value is calculated by NCBI based on data from submitters. Read our rules for calculating the review status.	Last evaluated Help The most recent date that a submitter evaluated this variant for the condition.	Variation/condition record Help The RCV accession number, with most recent version number, for the variant-condition record, with a link to the RCV web page.
not provided	Pathogenic (5)	criteria provided, multiple submitters, no conflicts	Oct 1, 2023	RCV000084436.28
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions	Pathogenic (1)	criteria provided, single submitter	Jan 29, 2021	RCV000767861.7
Neuronal ceroid lipofuscinosis 11	Pathogenic (1)	criteria provided, single submitter	Apr 24, 2020	RCV001291777.2
GRN-related frontotemporal lobar degeneration with Tdp43 inclusions Neuronal ceroid lipofuscinosis 11	Pathogenic (1)	criteria provided, single submitter	Jul 6, 2022	RCV001387934.6

Submissions - Germline

Classification Help The submitted germline classification for each SCV record. (Last evaluated)	Review status Help Stars represent the review status, or the level of review supporting the submitted (SCV) record. This value is calculated by NCBI based on data from the submitter. Read our rules for calculating the review status. This column also includes a link to the submitter’s assertion criteria if provided, and the collection method. (Assertion criteria)	Condition Help The condition for the classification, provided by the submitter for this submitted (SCV) record. This column also includes the affected status and allele origin of individuals observed with this variant.	Submitter Help The submitting organization for this submitted (SCV) record. This column also includes the SCV accession and version number, the date this SCV first appeared in ClinVar, and the date that this SCV was last updated in ClinVar.	More information Help This column includes more information supporting the classification, including citations, the comment on classification, and detailed evidence provided as observations of the variant by the submitter.
Pathogenic (May 11, 2020)	criteria provided, single submitter (Athena Diagnostics Criteria) Method: clinical testing	not provided Affected status: unknown Allele origin: unknown	Athena Diagnostics Accession: SCV001475245.1 First in ClinVar: Jan 26, 2021 Last updated: Jan 26, 2021	Publications: PubMed (11) PubMed: 31122931‚ 30528841‚ 25546130‚ 30279455‚ 29614680‚ 25525159‚ 17698705‚ 18245784‚ 20142524‚ 22312439‚ 23117491 Comment: The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one … (more) The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity. (less)
Pathogenic (Feb 21, 2022)	criteria provided, single submitter (GeneDx Variant Classification Process June 2021) Method: clinical testing	Not Provided Affected status: yes Allele origin: germline	GeneDx Accession: SCV000779672.4 First in ClinVar: Feb 20, 2014 Last updated: Mar 04, 2023	Comment: Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not … (more) Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also reported in an individual with a clinical diagnosis of posterior cortical atrophy with visual deficits, apperceptive visual agnosia, and occipital cortical atrophy (Caroppo et al., 2015); This variant is associated with the following publications: (PMID: 25525159, 29614680, 17698705, 30528841, 28749476, 30279455, 22312439, 25546130) (less)
Pathogenic (Jul 06, 2022)	criteria provided, single submitter (Invitae Variant Classification Sherloc (09022015)) Method: clinical testing	Neuronal ceroid lipofuscinosis 11 GRN-related frontotemporal lobar degeneration with Tdp43 inclusions Explanation for multiple conditions: Uncertain. The variant was classified for several related diseases, possibly a spectrum of disease; the variant may be associated with one or more the diseases. Affected status: unknown Allele origin: germline	Labcorp Genetics (formerly Invitae), Labcorp Accession: SCV001588693.4 First in ClinVar: May 10, 2021 Last updated: Feb 28, 2024	Publications: PubMed (6) PubMed: 17698705‚ 22312439‚ 30528841‚ 16862116‚ 16950801‚ 22608501 Comment: For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this … (more) For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 98134). This premature translational stop signal has been observed in individual(s) with clinical features of frontotemporal dementia (PMID: 17698705, 22312439, 30528841). This variant is present in population databases (rs63750411, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg110*) in the GRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRN are known to be pathogenic (PMID: 16862116, 16950801, 22608501). (less)
Pathogenic (Apr 24, 2020)	criteria provided, single submitter (NYGC Assertion Criteria 2020) Method: clinical testing	Neuronal ceroid lipofuscinosis 11 (Autosomal recessive inheritance) Affected status: unknown Allele origin: germline	New York Genome Center Study: CSER-NYCKidSeq Accession: SCV001480394.1 First in ClinVar: Feb 20, 2021 Last updated: Feb 20, 2021	Clinical Features: Autism (present) , Intellectual disability (present) , Seizure (present) , Delayed speech and language development (present) , Hypotonia (present) Secondary finding: no
Pathogenic (Jan 29, 2021)	criteria provided, single submitter (Classification criteria August 2017) Method: clinical testing	GRN-related frontotemporal lobar degeneration with Tdp43 inclusions (Autosomal dominant inheritance) Affected status: yes Allele origin: germline	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München Accession: SCV000897721.2 First in ClinVar: Apr 22, 2019 Last updated: Dec 24, 2022	Number of individuals with the variant: 1 Clinical Features: Frontotemporal cerebral atrophy (present) , Personality changes (present) , Aphasia (present)
Pathogenic (May 27, 2022)	criteria provided, single submitter (ACMG Guidelines, 2015) Method: clinical testing	not provided Affected status: yes Allele origin: germline	Clinical Genetics Laboratory, Skane University Hospital Lund Accession: SCV005198422.1 First in ClinVar: Aug 25, 2024 Last updated: Aug 25, 2024
Pathogenic (Oct 01, 2023)	criteria provided, single submitter (CeGaT Center For Human Genetics Tuebingen Variant Classification Criteria Version 2) Method: clinical testing	not provided Affected status: yes Allele origin: germline	CeGaT Center for Human Genetics Tuebingen Accession: SCV001250430.26 First in ClinVar: May 09, 2020 Last updated: Oct 20, 2024	Comment: GRN: PVS1, PM2 Number of individuals with the variant: 2
not provided (-)	no classification provided Method: not provided	not provided Affected status: not provided Allele origin: unknown	VIB Department of Molecular Genetics, University of Antwerp Accession: SCV000116572.1 First in ClinVar: Feb 20, 2014 Last updated: Feb 20, 2014 Comment: http://phencode.bx.psu.edu/cgi-bin/phencode/phencode?build=hg18&id=ADM_375

Comment:

The variant creates a premature nonsense codon, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and found in general population data at a frequency that is consistent with pathogenicity.

Comment:

Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Also reported in an individual with a clinical diagnosis of posterior cortical atrophy with visual deficits, apperceptive visual agnosia, and occipital cortical atrophy (Caroppo et al., 2015); This variant is associated with the following publications: (PMID: 25525159, 29614680, 17698705, 30528841, 28749476, 30279455, 22312439, 25546130)

Comment:

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 98134). This premature translational stop signal has been observed in individual(s) with clinical features of frontotemporal dementia (PMID: 17698705, 22312439, 30528841). This variant is present in population databases (rs63750411, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Arg110*) in the GRN gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in GRN are known to be pathogenic (PMID: 16862116, 16950801, 22608501).

Germline Functional Evidence

There is no functional evidence in ClinVar for this variation. If you have generated functional data for this variation, please consider submitting that data to ClinVar.

Comment:

Citations for germline classification of this variant

Title	Author	Journal	Year	Link
Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series.	Koriath C	Molecular psychiatry	2020	PMID: 30279455
Opposite microglial activation stages upon loss of PGRN or TREM2 result in reduced cerebral glucose metabolism.	Götzl JK	EMBO molecular medicine	2019	PMID: 31122931
Genetic analysis of neurodegenerative diseases in a pathology cohort.	Blauwendraat C	Neurobiology of aging	2019	PMID: 30528841
Novel GRN Mutations in Alzheimer's Disease and Frontotemporal Lobar Degeneration.	Piaceri I	Journal of Alzheimer's disease : JAD	2018	PMID: 29614680
Posterior cortical atrophy as an extreme phenotype of GRN mutations.	Caroppo P	JAMA neurology	2015	PMID: 25546130
RNA splicing. The human splicing code reveals new insights into the genetic determinants of disease.	Xiong HY	Science (New York, N.Y.)	2015	PMID: 25525159
Cognitive decline and reduced survival in C9orf72 expansion frontotemporal degeneration and amyotrophic lateral sclerosis.	Irwin DJ	Journal of neurology, neurosurgery, and psychiatry	2013	PMID: 23117491
Strikingly different clinicopathological phenotypes determined by progranulin-mutation dosage.	Smith KR	American journal of human genetics	2012	PMID: 22608501
Rare variants in APP, PSEN1 and PSEN2 increase risk for AD in late-onset Alzheimer's disease families.	Cruchaga C	PloS one	2012	PMID: 22312439
The spectrum of mutations in progranulin: a collaborative study screening 545 cases of neurodegeneration.	Yu CE	Archives of neurology	2010	PMID: 20142524
Phenotype variability in progranulin mutation carriers: a clinical, neuropsychological, imaging and genetic study.	Le Ber I	Brain : a journal of neurology	2008	PMID: 18245784
Clinical, genetic, and pathologic characteristics of patients with frontotemporal dementia and progranulin mutations.	Van Deerlin VM	Archives of neurology	2007	PMID: 17698705
Mutations in progranulin are a major cause of ubiquitin-positive frontotemporal lobar degeneration.	Gass J	Human molecular genetics	2006	PMID: 16950801
Mutations in progranulin cause tau-negative frontotemporal dementia linked to chromosome 17.	Baker M	Nature	2006	PMID: 16862116
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Text-mined citations for rs63750411 ...

These citations are identified by LitVar using the rs number, so they may include citations for more than one variant at this location. Please review the LitVar results carefully for your variant of interest.

Record last updated Oct 20, 2024

ClinVar Genomic variation as it relates to human health

NM_002087.4(GRN):c.328C>T (p.Arg110Ter)

Variant Details

Genes

Conditions - Germline

Submissions - Germline

Germline Functional Evidence

Citations for germline classification of this variant

Text-mined citations for rs63750411 ...